2-Amino-5-chloro-1 H -pyrrole-3,4-dicarbonitrile

: The reaction of tetracyanoethylene (TCNE) with HCl (g) in the presence of Sn (1 equiv) and AcOH resulted in 2-amino-5-chloro-1 H -pyrrole-3,4-dicarbonitrile in a 74% yield. The compound was fully characterized.


Introduction
Pyrroles are important aromatic N-heterocycles that exist in nature, for example, as components of the well-known ligand heme (Figure 1).Pyrroles also have wide pharmaceutical applications with examples of pyrrole containing drugs being the nonsteroidal anti-inflammatory drug tolmetin and the lipid-lowering agent atorvastatin (Figure 1).Other uses of pyrroles include insecticides [1], dyes [2] and polymers [3].The chemistry of pyrroles has been reviewed [4].

Introduction
Pyrroles are important aromatic N-heterocycles that exist in nature, for example, as components of the well-known ligand heme (Figure 1).Pyrroles also have wide pharmaceutical applications with examples of pyrrole containing drugs being the nonsteroidal anti-inflammatory drug tolmetin and the lipid-lowering agent atorvastatin (Figure 1).Other uses of pyrroles include insecticides [1], dyes [2] and polymers [3].The chemistry of pyrroles has been reviewed [4].
Scheme 2. The claimed patented synthesis of chloropyrrole 3 and its use to prepare ylidene 5.
The reaction involved bubbling HCl (g) through a solution of TCNE in Me2CO, EtOAc and AcOH, followed by the addition of powdered Sn (1 equiv) (Scheme 3).The choice of this solvent mixture was inspired by a reported preparation of the bromopyrrole 6 [16], as it dissolves the reagents effectively but does not dissolve the HCl salt of the product 3, thereby allowing for a facile purification of the product after the end of the reaction by filtration and subsequent treatment with base and acid (see materials and methods below).The addition of the reductant Sn (in the presence of AcOH) was required to bring the product to the correct oxidation state.In contrast, no reductant was required in the reported synthesis of bromopyrrole 6 [15], tentatively, due to a redox reaction involving loss of Br2.Subsequent stirring for 2 h resulted in a yellow precipitate, presumably the HCl salt of aminopyrrole 3.An acid/base treatment involving first 2 M NaOH and then AcOH resulted in the desired compound 3 in a 74% yield (see supplementary materials for the complete spectra).The chloropyrrole 3 appears in the patent literature where it is claimed to be synthesized in a three-step synthesis starting from 1H-pyrrole-3,4-dicarbonitrile (4) (Scheme 2), but no experimental details or characterization data are reported [6][7][8][9][10][11][12][13][14].Interestingly, the chloropyrrole 3 was used as a scaffold for the synthesis of dyes, such as ylidene 5 (Scheme 2), used in color photography [6][7][8][9][10][11][12][13][14], while it is also commercially available (CAS: 152586-70-4).
Scheme 2. The claimed patented synthesis of chloropyrrole 3 and its use to prepare ylidene 5.
The reaction involved bubbling HCl (g) through a solution of TCNE in Me2CO, EtOAc and AcOH, followed by the addition of powdered Sn (1 equiv) (Scheme 3).The choice of this solvent mixture was inspired by a reported preparation of the bromopyrrole 6 [16], as it dissolves the reagents effectively but does not dissolve the HCl salt of the product 3, thereby allowing for a facile purification of the product after the end of the reaction by filtration and subsequent treatment with base and acid (see materials and methods below).The addition of the reductant Sn (in the presence of AcOH) was required to bring the product to the correct oxidation state.In contrast, no reductant was required in the reported synthesis of bromopyrrole 6 [15], tentatively, due to a redox reaction involving loss of Br2.Subsequent stirring for 2 h resulted in a yellow precipitate, presumably the HCl salt of aminopyrrole 3.An acid/base treatment involving first 2 M NaOH and then AcOH resulted in the desired compound 3 in a 74% yield (see supplementary materials for the complete spectra).
Scheme 2. The claimed patented synthesis of chloropyrrole 3 and its use to prepare ylidene 5.
The reaction involved bubbling HCl (g) through a solution of TCNE in Me 2 CO, EtOAc and AcOH, followed by the addition of powdered Sn (1 equiv) (Scheme 3).The choice of this solvent mixture was inspired by a reported preparation of the bromopyrrole 6 [16], as it dissolves the reagents effectively but does not dissolve the HCl salt of the product 3, thereby allowing for a facile purification of the product after the end of the reaction by filtration and subsequent treatment with base and acid (see materials and methods below).The addition of the reductant Sn (in the presence of AcOH) was required to bring the product to the correct oxidation state.In contrast, no reductant was required in the reported synthesis of bromopyrrole 6 [15], tentatively, due to a redox reaction involving loss of Br 2 .Subsequent stirring for 2 h resulted in a yellow precipitate, presumably the HCl salt of aminopyrrole 3.An acid/base treatment involving first 2 M NaOH and then AcOH resulted in the desired compound 3 in a 74% yield (see Supplementary Materials for the complete spectra).Chloropyrrole 3 was subsequently reacted with tetrachlorothiadiazine 2 in attempts to synthesize tricycle 1.However, while the respective reaction of bromopyrrole 6 with tetrachlorothiadiazine 2 was clean and resulted in thiadiazinimine 7 in excellent yield, which was subsequently converted to tricycle 8 [5], the reaction of chloropyrrole 3 in a number of different conditions [MeCN at 20-82 °C; MeCN, 2,6-lutidine (1 eq) at 20 °C; DCE at 83 °C; THF at 20-66 °C; PhCl at 132 °C] only resulted in a complex mixture of products that could not be resolved (Scheme 4).

Figure 1 .
Figure 1.Pyrroles in nature and in drugs.

Figure 1 .
Figure 1.Pyrroles in nature and in drugs.